Thiocarbhydrazine compounds



Patented Apr. 6, 1954 THIOCARBHYDBAZINE COMPOUNDS Jiirgen A. Wangel,Saltsjo-Duvnas, Sweden, as-

signor to Aktiebolaget Pharmacia, Uppsala, Sweden, a company of SwedenNo Drawing. Application August 8, 195%, Serial No. 178,350

Claims priority, application Sweden August 17, 1949 6 Claims.

tain thiocarbhydrazine compounds have proved to possess a good activityon experimental tuberculosis and as, furthermore, they show a favourabletoxicity, they are well suited to be used as chemotherapeutica.

These new compounds according to the invention have the general formulaR: r where R1 is a benzyl or a cyclohexyl radical, R3 is a radicalselected from the group consisting of CSO-CeH11 and hydrogen, R3 and R2taken together may present =CHCsHs, Re otherwise representing hydrogen;R1 being cyclohexyl when R3 is hydrogen.

These particular compounds possess a unique property in that they havelow toxicity for both healthy and tubercular mice. In contrast such aclosely related compound as N -benzoxythiocarbonyl-N -pheny1hydrazine,in which R3 is a benzene radical, while being non-toxic for healthy miceis toxic for tubercular mice and consequently would not be suitable foruse in treating experimental tuberculosis in mice.

These new tuberouloactive compounds according to the invention may beproduced either by the introduction into compounds, in which the radical1 is present, of the radical R1.O.CS.-, or by the. introduction intocompounds, in which the radical R1.O.CS.NH.N-- is present, of R2 and/orR3, or by the introduction into compounds, in which the group ispresent, by treatment with reactive derivatives of R10, of the radical Ror, finally, in the case that R3 is the same as R1O.CS., by theintroduction simultaneously into hydrazine of two identicaloxythiocarbonyl radicals.

Thus, xantogen hydrazides are reacted with carbonyl compounds (forexample an aldehyde, an acid halogenide or a carbonyl-thio-glycolicacid) or with a xantogenic acid, its salts or reactive derivatives.Substituted hydrazines with a free NHz-group may be reacted withXantogenic acids, their salts or reactive derivatives, respectively, andthe same also applies to hydrazine, its hydrate and salts, respectively.

N -substituted N -thionthiol carbonic acid hydrazines, their salts orreactive derivatives, respectively, may be reacted with benzyl alcoholor cyclohexyl alcohol, their alcoholates or reactive derivatives,respectively. Substituted thionthiol carbonic acid esters may be reactedwith substituted or not substituted hydrazine, its salts or hydrate,respectively.

The following examples illustrate the invention without restricting thsame.

Example 1 18 gms. sodium are boiled in 500 ml. dry cyclohexanol untildissolution has taken place. After cooling the cake thus formed isground and then suspended in 2.1 ether and boiled for 15 minuteswhereupon 64 gms. carbon bisulphide are added. The mixture is thenboiled further for 45 minutes and extracted with 1 1. water. The extractis reacted at room temperature with 40 gms. hydrazine hydrate and herebycyclohexoxythiocarbonyl hydrazine precipitates which afterrecrystallization from benzene/petroleum ether is obtained in a yield ofgms. with a M. Pt. '76-7'7 C.

Instead of using hydrazine hydrate a salt thereof may be employed inwhich case this may suitably be neutralized with caustic alkali.

Ewample 2 To 1.8 gms. benzoxythiocarbonyl hydrazine in 5 ml. ethylalcohol (95%) are added 1.1 gms. benzaldehyde in 5 ml. ethyl alcohol andhereby benzaldehyde benzoxythiocarbonyl hydrazone precipitates at roomtemperature in the form of narrow crystal prisms which afterrecrystallization from benzene have the M. Pt. 1 4-1245 C.

Example 3 To 0.3 mol benzyl xantogen acetic acid in ml. ethyl alcohol(95%) is added the equivalent amount 5-n caustic alkali together with0.14 mcl hydrazine hydrate. After standing for 3 hours at roomtemperature prismatic crystals of N ,N

3 di-benzoxythiocarbonyl hydrazine with the M. Pt. 118-119.5 C. begin toprecipitate.

Example 4 To 4 gms. benzoylthioglycolic acid in 20 ml. l-n causticalkali are added 3.5 gms. cyclohexoxythiocarbonyl hydrazine in 20 ml.ethyl alcohol (95%) and hereby N -benzoyl-N -cyclohexoxythiocarbonylhydrazine gradually precipitates as prismatic crystals with a M. Pt.120.5-122.5 C.

Example 5 To 18 gms. cyclohexoxythiocarbonyl hydrazine in 60 ml. ethylalcohol (95%) are added 9.7 ml. acetic acid anhydride and hereby in ashort time N -acetyI-N -cyclohexoxythiocarbonyl hydrazine precipitatesin the form of prismatic crystals with a M. Pt. 138-140 C.

In a corresponding manner N -benzoyl-N -cyclohexoxythiocarbonylhydrazine is obtained when using for instance benzoyl chloride insteadof acetic anhydride.

In an analogous manner also the following compounds may be produced:

Benzaldehyde-cyclo-hexoxythiocarbony1 hydra zone,

CsH11O.CS.NH.N=CH.CsH5

N cyclohexoxythiocarbonyl N acetyl hydrazine,

CeH110.CS.NH.NH.CO.CI-I3 N -benzoxythiocarbonyl-N -acetyl-hydrazine,

CsH5CI-L O.CS.NH.NH.CO.CH3

N cyclohexoxythiocarbonyl N benzoyl hydrazine,

CeH110.CS.NH.NH.CO.CsH5

N -benzoxythiocarbony1-N=-benzoyl-hydrazine,

CeH5CH2O.CS.NH.NH.CO.CsH5

N benzoxythiocarbonyl N cyclohexoxythiccarbonyl-hydrazine,

C6H5CH20.Cs.NH.NH.CS.O-CGH11 NAN -di-cyclohexoxythiocarbonyl-hydrazine,

CsHnO.CS.NH.NH.CS.O.C6H11 I claim: 1. Thiocarbhydrazine compounds of thegeneral formula where R1 is a radical selected from the group consistingof benzyl and cyclohexyl radicals, R3 is a radical selected from thegroup consisting of 'CO'CcH5, CO-CH:, -CS-O--CH2CeH5, CSO-CsH11 andhydrogen, R3 and R2 taken together may represent =CHC6H5, R2 otherwiserepresenting hydrogen; R1 being cyclohexyl when R3 is hydrogen.

2. The new compound benzaldehyde-benzoxythiocarbonyl-hydrazone.

3. The new compound benzaldehyde-cyclohexoxythiocarbonyl-hydrazone.

4. The new compound N -cyclohexoxythiocarbonyl-N -benzoyl-hydrazine.

5. The new compound N ,N -di-benzoxythiocarbonyl-hydrazine.

6. The new compound N ,N -di-cyc1ohexoxythiocarbonyl-hydrazine.

References Cited in the file of this patent Bulmer: J. Chem. Soc.(1945), pages 666-674.

1. THIOCARBHYDRAZINE COMPOUNDS OF THE GENERAL FORMULA